rs763841075

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS1

The NM_002087.4(GRN):c.415T>C(p.Cys139Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,612,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

GRN
NM_002087.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 5.06

Publications

45 publications found

Variant links:

Genes affected

GRN (HGNC:4601): (granulin precursor) Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis. [provided by RefSeq, Jul 2008]

GRN Gene-Disease associations (from GenCC):

frontotemporal dementia and/or amyotrophic lateral sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
neuronal ceroid lipofuscinosis 11
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P

GRN links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002087.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000146 (214/1461708) while in subpopulation MID AF = 0.00416 (24/5768). AF 95% confidence interval is 0.00287. There are 0 homozygotes in GnomAdExome4. There are 111 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	NM_002087.4	MANE Select	c.415T>C	p.Cys139Arg	missense	Exon 5 of 13	NP_002078.1	P28799-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRN	ENST00000053867.8	TSL:1 MANE Select	c.415T>C	p.Cys139Arg	missense	Exon 5 of 13	ENSP00000053867.2	P28799-1
GRN	ENST00000900927.1		c.415T>C	p.Cys139Arg	missense	Exon 5 of 13	ENSP00000570986.1
GRN	ENST00000900929.1		c.415T>C	p.Cys139Arg	missense	Exon 6 of 14	ENSP00000570988.1

Frequencies

GnomAD3 genomes

AF:

0.0000992

AC:

AN:

151196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.000179

AC:

AN:

251476

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000146

AC:

214

AN:

1461708

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000313

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000124

AC:

138

AN:

1111848

Other (OTH)

AF:

0.000182

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000992

AC:

AN:

151196

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

73754

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41030

American (AMR)

AF:

0.000132

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000209

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67838

Other (OTH)

AF:

0.000484

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000212

Hom.:

Bravo

AF:

0.000121

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 (2)

GRN-related disorder (1)

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.9

PhyloP100

5.1

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

PromoterAI

0.034

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.98

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over